Levetiracetam is an antiepileptic drug available as immediate and extended release tablets for oral administration. Its chemical name is (αS)-α-Ethyl-2-oxo-1-pyrrolidineacetamide and its chemical structure is shown in the Formula I.

Extended release dosage form of levetiracetam is marketed under the brand name Keppra XR™ and it is administered orally in a therapeutic dose of 500 mg and 750 mg.
Levetiracetam is indicated as adjunctive therapy in the treatment of partial onset seizures in adults with epilepsy. It is recommended that such treatments should be initiated with a daily dose of 1000 mg once daily. Additional dose increments may be given so as to reach a maximum recommended daily dose of 3000 mg. Currently commercially available tablets are available in strengths of 500 mg and 750 mg of levetiracetam, making it very inconvenient for the patient to comply with the dosing regimen prescripted, particularly when the patient may be stabilized at the higher daily dose.
Levetiracetam is a rapidly soluble active ingredient and almost completely absorbed after oral administration, so it is difficult to slow down the release without causing dose dumping and to formulate levetiracetam as an extended release pharmaceutical composition especially comprising high amounts of about 500 mg to 1500 mg per tablet for once daily or twice daily dosing.
In the prior art, there are many patents including levetiracetam in several different modified release pharmaceutical compositions, for example in PCT application, WO 2006/088864 A1, Elan Pharma Int. Ltd., Feb. 2, 2005, a controlled release composition of levetiracetam is disclosed which comprises an immediate release component and a modified release component or formulation. The modified release component or formulation is preferably in the form of an erodable formulation, a diffusion controlled formulation or an osmotic controlled formulation.
WOO151033 A1, UCB S.A., Jan. 14, 2000, provides a solid pharmaceutical compound that can be administered orally, permitting controlled release of at least one active substance which can be levetiracetam consisting of a homogeneous mixture comprising active substance, at least one matrix excipient between 5 and 95% by weight of the total weight of the compound, selected among the inert matrices, the hydrophilic, or lipid matrices, mixtures of inert and lipidic matrices mixture of hydrophilic and inert matrices; at least one entero-soluble polymer between 2 and 50% by weight of the total weight of the compound and at least one alkalinizing agent soluble in a aqueous phase under conditions of physiological pH, of at least 0.5 to 50% by weight of the total weight of the compound.
PCT application WO 2006/080029 A1, Alembic Ltd., 27.01.2005, relates to an extended release pharmaceutical composition of levetiracetam with once a day dosage regimen and the process of preparing it. The composition is preferably in the form of a coated tablet. The extended release tablet of levetiracetam with the core comprising of levetiracetam and water dispersible rate controlling polymer, and the tablet core optionally functional coated comprising a combination of water non-dispersible and/or water dispersible polymer.
PCT application WO 2006/123357 A2, Sun Pharmaceutical Industries Ltd.HHH Feb. 22, 2005, relates to an oral controlled release pharmaceutical composition in the form of a unit dosage form comprising: (a) therapeutically effective amount of levetiracetam or pharmaceutically acceptable salts thereof, and (b) a rate controlling means comprising a rate-controlling agent and/or a coating selected from a (i) active ingredient permeable coating surrounding the unit dosage form, and (ii) an active ingredient impermeable coating covering one or more surfaces but not all the surfaces of the unit dosage form, wherein the composition is in the form of a compact tablet and the levetiracetam or pharmaceutically acceptable salts thereof is present in an amount ranging from 55% to 90% by weight of the tablet.
PCT application WO 2008/006528 A2, UCB Pharma S.A., Jul. 13, 2006, discloses a prolonged release composition in the form of a tablet comprising as an active ingredient, levetiracetam, and as an excipient within the core of the tablet, 5.0 to 59.0% per weight of at least one hydrophilic matrix agent such as hydroxypropyl methylcellulose, with respect to the total weight of the core of the tablet. The most preferably the range is 25.0 to 28.0% per weight of hydrophilic matrix agent, with respect to the total weight of the core of the tablet. Furthermore, the tablet is coated with a hydrophilic polymer such as Opadry™.
Another PCT application WO 2008/062446 A2, Alembic Ltd., 14.09.2006, provides an extended release composition of levetiracetam, which exhibits no adverse food effect, comprising from about 30% w/w to about 85% w/w of levetiracetam and about 1% w/w to about 50% w/w of the composition of a water dispersible rate controlling polymer, wherein the composition is in tablet form and said tablet is coated with a functional coat of about 1% w/w to 15% w/w of the tablet weight comprising a combination of a water non dispersible polymer and a water dispersible polymer. The preffered rate controlling polymer is hydroxypropyl methylcellulose, which is in the range of 20 to 40% by weight of the total tablet composition.
These patent applications described above disclose modified release (eg. extended, prolonged, controlled release) pharmaceutical compositions of levetiracetam comprising rate controlling polymers particularly, hydroxypropyl methylcellulose which has an amount of min. 20% by weight of the total composition, and mostly have a coating and preferably the coating has one or two rate controlling agent. In this present invention, the solution to these problems described above is having a smaller quantity of the excipients and rate controlling polymers to obtain the extended release and to prevent dose dumping of pharmaceutical composition of the active ingredient, levetiracetam, such as previously not disclosed in prior art.
In this present invention, to obtain the extended release of levetiracetam, hydrophilic polymers, such as hydroxypropyl methylcellulose, are not used in high concentrations; on the other hand this may cause dose dumping. Dose dumping is one of the most important disadvantages of extended release dosage forms. Extended release formulations of highly soluble medicaments can be prone to “dose dumping” in which the release of the active ingredient is delayed, but once the release begins the medicament is released very fast. The most important criteria of dose dumping under in-vitro conditions, is the amount of the active substance released in early time point. In the prior art, to prevent dose dumping especially hydroxypropyl methylcellulose is used in high concentrations, e.g., greater than about 20% (w/w) of the dosage form and in a weight ratio greater than 1:1 relative to the drug.
Another problem is the requirement to have compact tablets that are easily swallowable; it is known that for extending the release rate of rapidly dissolved active ingredients which are also effective in higher therapeutic amounts such as levetiracetam, a large quantity of excipients are used, including the rate controlling agents. These large quantities of excipients necessary for adequate extended release of the active ingredient can make the production of the dosage form impossible or too costly. Moreover, in that case the tablet size may be too large so that the tablet cannot be swallowed.
Accordingly, a need rises for extended release formulations of levetiracetam or pharmaceutically acceptable salts thereof, which overcomes the above described problems and minimizes the adverse effects and provides a bioavailable pharmaceutical composition according to the formulations currently used. The formulation of this invention represents a novel extended release pharmaceutical composition of levetiracetam previously undisclosed in the prior art.